Hybridomas (fused cells) are used in producing substances using culture cells. There are many animal cells that produce commercially or academically useful substances. However, it is in general difficult to culture animal cells, and there is no technique for stably culturing animal cells for a long period while maintaining their ability to produce substances. Under such circumstances, a technique was proposed to create cells comprising both characteristics of the ability to grow in culture and the ability to produce substances. With this technique, hybridomas are made by fusing cells producing a biologically active substance and, as fusion partner cells, myeloma cells that can be passaged indefinitely and stably in vitro.
When monoclonal antibodies are produced by the cell fusion method, hybridomas are tested for their characteristics such as antibody productivity and binding activity and the selected cells are cloned to homogeneity. Then, the cells are grown to homogeneous cell populations to produce monoclonal antibodies. Such hybridomas are grown by in vitro or in vivo (in ascites) cultures and expanded to produce antibodies on a large scale. The method for developing monoclonal antibodies using the cell fusion method is already known (see Non-Patent Document 1). Monoclonal antibodies are believed to be more superior in specificity as compared to polyclonal antibodies purified from antisera. Thus, monoclonal antibodies are used as a powerful tool in various immunological assay methods.
When cells from the same species are fused, the fused cells are simply called “hybridomas”. In general, mouse monoclonal antibodies and the like are produced by this method. On the other hand, antibody-producing cells obtained by fusing cells isolated from a particular species with immortalized cells derived from a different species are called “heterohybridomas”. The term “heterohybrid” is synonymous with heterologous fusion, and the produced cells are called “heterohybridomas”. Furthermore, antibody-producing cells produced by fusing cells derived from three animal species are called “triomas”. Monoclonal antibodies produced by this method are rat and hamster antibodies. Heterohybridomas between mouse and rat or between mouse and hamster are produced by fusing mouse myeloma cells with lymphocytes derived from rats or hamsters to which an antigen of interest has been administered. Heterohybridomas thus obtained are cloned and provide monoclonal antibodies which are derived from each immunized animal.
To date, reports have been published on heterohybridomas producing human, rabbit, bovine, and sheep monoclonal antibodies (see Non-Patent Documents 2 to 5 and Patent Documents 1 and 2).
However, monoclonal antibody production by heterohybridomas is considered to be more difficult as the phylogenetic distance between the species of cells to be fused increases. For example, it is extremely difficult to produce antibodies using hybridomas between mouse and rabbit, or mouse and human. Since hybridomas have an aberrant number of chromosomes, segregation does not always distribute the same chromosome pairs to the daughter cells and some chromosomes may be lost.    Non-Patent Document 1: Waldman, T., Science 252:1657-1662 1991    Non-Patent Document 2: Proc. Natl. Acad. Sci. USA 80:7308-7312, 1983    Non-Patent Document 3: Raybould et al., Science 240:1788-1790, 1988    Non-Patent Document 4: Kennedy et al., J. Gen. Virol. 69:3023-3032, 1988    Non-Patent Document 5: Flynn et al., J. Immunol. Methods 121:237-246, 1989    Patent Document 1: U.S. Pat. No. 4,634,664 specification    Patent Document 2: U.S. Pat. No. 4,977,081 specification